PI-103, as a potent class I PI3K inhibitor

by Selleckchem | Oct 21 2012

CHARACTERIZATION of PI-103
So far, there are a lot of PI3K isozyme-selective allosteric inhibitors that have been reported. For example, PIK-75 is a p110alpha-specific inhibitor, TGX-221 is a p110beta-specific inhibitor andIC87114 is a p110delta-specific inhibitor. These PI3K inhibitors are promising agents in the treatment of cancer and other diseases, and PI-103 is one of them. PI-103 is a potent, cell-permeable, ATP-competitive class I PI3K inhibitor. The structure analysis indicates that PI-103 is a pyridinylfuranopyrimidine molecule and ATP-competitive PI3K inhibitor. PI-103 has the solubility around 24 mg/mL in both dimethyl sulfoxide (DMSO), however it is scarcely soluble in ethanol and water with solubility of less than 1 mg/mL. And the approximate price of PI-103 is $151 per 10 mg and $466 per 50 mg in selleckchem.com, and PI-103 price may vary according to the proportion purity of the preparation and/or from one PI-103 supplier to different ones.

IN VITRO ACTIVITIES
Kinase assays demonstrates that PI-103 shows potent inhibitory activities against recombinant PI3K isoforms including p110-alpha, p110-beta, p110-delta, and p110-gamma with IC50 of 2 nmol/L, 3 nmol/L, 3 nmol/L and 15 nmol/L, respectively. At the same time,PI-103 also inhibited the activities of DNA-PK with IC50 of 14 nmol/L, and inhibits mTORC1 by 83.9%at 0.5 μmol/L. [1] In vitro, PI-103 treatment results in a time- and concentration-dependent decrease in phosphorylation of AKT Ser473 and Thr308 and GSK3β Ser9 in a panel of human cancer cell lines such as HCT116 human colorectal carcinoma, U87MG glioblastoma and PC3 prostate cancer cells. Consistent with inhibition of PI3K signaling, PI-103 potently inhibits proliferation and invasion of a wide variety of human cancer cells. [1] In respect to combination application, cooperative inhibition of EGFR and mTOR by erlotinib and PI-103 lead to increased arrest growth of PTEN mt human glioma cells. [2] Combination treatment of PI-103 and radiation enhances the G(2)-M delay observed after irradiation in cancer cells. [3] In hepatocellular carcinoma (HCC), PI-103 in combination with sorafenib significantly inhibit EGF-stimulated Huh7 proliferation by blocking both Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. [4]

IN VIVO ACTIVITIES
In vivo, PI-103 exhibits potent antitumor activity in mice bearing PTEN null U87MG glioblastoma, PC3 prostate, and MDA-MB-468 breast carcinomas and the PIK3CA mutant HCT 116 colon carcinoma cells. Moreover, PI-103 also produces inhibitory effects on cell migration, invasion, and angiogenesis. [1] In respect to combination therapy, combination of Sorafenib and PI-103 are demonstrated to more efficiently inhibits tumorigenesis as compared to mono-drug treatments. [5] These studies support the potential clinical use of PI-103 as a partner for conventional drugs. The studies of clinical trails about PI-103 has been elaborated in the previous article.